Stereoselective Synthesis of the Key Intermediates of the HIV Protease Inhibitor Fosamprenavir and Its Diastereomer

Illia Panov; Pavel Drabina; Jiří Hanusek; Miloš Sedlák

doi:10.1055/s-0033-1338803

Synlett, Table of Contents

Synlett 2013; 24(10): 1280-1282
DOI: 10.1055/s-0033-1338803

letter

Stereoselective Synthesis of the Key Intermediates of the HIV Protease Inhibitor Fosamprenavir and Its Diastereomer

Illia Panov

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic Fax: +420(466)037068 Email: milos.sedlak@upce.cz

,

Pavel Drabina

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic Fax: +420(466)037068 Email: milos.sedlak@upce.cz

,

Jiří Hanusek

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic Fax: +420(466)037068 Email: milos.sedlak@upce.cz

,

Miloš Sedlák*

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic Fax: +420(466)037068 Email: milos.sedlak@upce.cz

› Author Affiliations

Abstract

All articles of this category

In memory of Professor RNDr. Antonín Holý, DrSc., dr.h.c.

Abstract

Highly stereoselective Henry reaction has been used in the synthesis of the fosamprenavir precursor (2S,3R)-N-tert-butyloxycarbonyl-2-amino-3-hydroxy-1-phenyl-4-nitrobutane and its 2S,3S diasteromer from N-tert-butyloxycarbonyl-(S)-phenylalaninal and nitromethane. The complex of (2S,5R)- or (2R,5S)-5-isopropyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-one with copper(II) acetate has been used as the catalyst which provided the product with 2S,3R absolute configuration (dr = 90:10, overall yield 89%) or 2S,3S (dr = 99:1, overall yield 94%), respectively.

Key words

aldol reaction - diastereoselectivity - HIV - homogenous catalysis - ligands

Full Text

References

References and Notes
1 De Clercq E, Descamps J, De Somer P, Holý A. Science 1978; 200: 563
2 Kim EE, Baker CT, Dwyer MD, Murcko MA, Rao BG, Tung RD, Navia MA. J. Am. Chem. Soc. 1995; 117: 1181
3 De Clercq E. Rev. Med. Virol. 2009; 19: 287
4 Kaldor SW, Kalish VJ, Davies JF. II, Shetty BV, Fritz JE, Appelt K, Burgess JA, Campanale KM, Chirgadze NY, Clawson DK, Dressman BA, Hatch SD, Khalil DA, Kosa MB, Lubbehusen PP, Muesing MA, Patick AK, Reich SH, Su KS, Tatlock JH. J. Med. Chem. 1997; 40: 3979
5 Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galphin SA, Handa BK, Krohn A, Lambert RW, Merrett JH, Mills JS, Parkes KE. B, Redshaw S, Ritchie AJ, Taylor DL, Thomas GJ, Machin PJ. Science 1990; 248: 358
6 Honda Y, Katayama S, Kojima M, Suzuki T, Kishibata N, Izawa K. Org. Biomol. Chem. 2004; 2: 2061
7 Corey EJ, Zhang F.-U. Angew. Chem. Int. Ed. 1999; 38: 1931
8 Gadakh SK, Reddy RS, Sudalai A. Tetrahedron: Asymmetry 2012; 23: 898
9 Kim BM, Bae SJ, So SM, Yoo HT, Chang SK, Lee JH, Kang JS. Org. Lett. 2001; 3: 2349
10 Nogami H, Kanai M, Shibasaki M. Chem. Pharm. Bull. 2003; 51: 702
11 Arai T, Taneda Y, Endo Y. Chem. Commun. 2010; 46: 7936
12 Sasai H, Kim W.-S, Suzuki T, Shibasaki M. Tetrahedron Lett. 1994; 35: 6123
13 Palomo C, Oiarbide M, Laso A. Eur. J. Org. Chem. 2007; 2561
14 Reddy BV. S, Reddy SM, Manisha S, Madan C. Tetrahedron: Asymmetry 2011; 22: 530
15 Xu K, Lai G, Zha Z, Pan S, Chen H, Wang Z. Chem. Eur. J. 2012; 18: 12357
16 Sedlák M, Drabina P, Keder R, Hanusek J, Císařová I, Růžička A. J. Organomet. Chem. 2006; 691: 2623
17 Panov I, Drabina P, Padělková Z, Šimůnek P, Sedlák M. J. Org. Chem. 2011; 76: 4787
18 Drabina P, Karel S, Panov I, Sedlák M. Tetrahedron: Asymmetry 2013; 24: 334
19 One of the ligands L1 or L2 (0.055 mmol) and Cu(OAc)₂ (9.1 mg, 0.05 mmol) were stirred for 1 h in a mixture of EtOH (1.5 mL) and MeNO₂ (0.54 mL, 10 mmol) at r.t. to generate the catalyst. The solution was cooled to 18 °C, and then the aldehyde (1 mmol) was added. The mixture was stirred for the 96 h, the solvents were removed under reduced pressure, and the product was purified by short flash chromatography using EtOAc as an eluent.
20 The diastereomeric ratio of 4c/5c was determined by HPLC with a Chiralcel AD-H column [hexane–isopropyl alcohol (90:10), 0.8 mL/min, 254 nm]: t _R (5c) = 12.1 min; t _R (4c) = 23.1 min.
21 Compound 5c: yield 291 mg (94%); mp 168–170 °C. ¹H NMR (400 MHz, DMSO-d₆ , 75 °C): δ = 7.28–7.15 (m, 5 H, ArH), 6.47 (br s, 1 H, NH), 5.51 (d, J = 6.9 Hz, 1 H, OH), 4.67 (dd, J = 12.5, 3.0 Hz, 1 H, CH₂), 4.39 (dd, J = 12.5, 9.2 Hz, 1 H, CH₂), 4.19–4.10 (m, 1 H, CH_OH), 3.69–3.61 (m, 1 H, CH_NH), 3.02 (dd, J = 13.5, 3.8 Hz, 1 H, CH₂), 2.62 (dd, J = 13.5, 10.1 Hz, 1 H, CH₂), 1.28 (s, 9 H, t-Bu). ¹³C NMR (100 Mz, DMSO-d ₆): δ = 155.4, 139.0, 129.2, 128.1, 125.9, 80.0, 77.9, 71.2, 54.7, 36.0, 28.2.
22 Compound 4c: yield 280 mg (89%); mp 133–134 °C. ¹H NMR (400 MHz, DMSO-d ₆, 75 °C): δ = 7.28–7.17 (m, 5 H, ArH), 6.31 (br s, 1 H, NH), 5.42 (d, J = 6.6 Hz, 1 H, OH), 4.67 (dd, J = 12.5, 2.0 Hz, 1 H, CH₂), 4.37–4.32 (m, 1 H, CH₂), 4.23–4.19 (m, 1 H, CH_OH), 3.79–3.77 (m, 1 H, CH_NH), 2.88 (dd, J = 13.7, 5.1 Hz, 1 H, CH₂), 2.66 (dd, J = 13.6, 9.4 Hz, 1 H, CH₂), 1.31 (s, 9 H, t-Bu). ¹³C NMR (100 Mz, DMSO-d ₆): δ = 155.4, 139.0, 129.2, 128.2, 126.1, 79.5, 78.0, 69.8, 54.4, 35.7, 28.2.